Human immunodeficiency virus type- I (HIV-1) infection can lead to a series of devastating clinical conditions in the central nervous system (CNS) of certain HIV-1-infected individuals. AIDS dementia complex (ADC) is a collective term to describe AIDS-related cognitive dysfunction, motor difficulties, coordination abnormalities and other neurological signs and symptoms. Blood-brain barrier mainly constituted of micro vascular endothelial cells (MVECs) a protective sheath is a potential obstacle for conventional antiretroviral penetration into the brain. Gene therapy is one the most promising avenues for treatment of neurodegenerative disorders in general and AIDS dementia in particular. Our laboratories in recent past have utilized retroviral vectors for gene delivery in CNS based cells both in vitro and in vivo. Cell-type-specific gene delivery into distinct cells of the central nervous system will be one of the major prerequisites for successful human gene therapy of neurological disorders. In the past decade, Dr. Dornburg's laboratory has gained extensive experience in the construction of cell-type-specific retroviral vectors, derived from the avian reticuloendotheliosis viruses REV-A and spleen necrosis virus, SNV, which display single chain antibodies (scAs) or other targeting ligands on the viral surface. Moreover, pseudotyping REV-derived vectors with the envelope protein of a neurotropic rabies virus strain enabled cell-type-specific gene delivery into neurons in vitro and in vivo. The main goals of this research project are the further development of retroviral vectors, which enable cell-type-specific gene delivery into neurons and brain MVECs. A series of novel retroviral vectors will be developed which transduce therapeutic genes useful for gene therapy of AIDS dementia. The vector design will enable expression of the therapeutic gene from cell-type-specific or inducible promoters. These vectors will be tested in vitro and in vivo. In vitro testing include long-term studies of the efficiency of the therapeutic gene, microarray assays to determine changes of normal gene expression in neurons or brain MVECs, and the testing of the vectors in vitro blood brain barrier systems. Dr. Mukhtar has extensive experience in this area. In vivo experiments will be performed in mice to test long-term gene expression and to determine whether macroscopic or microscopic changes occur in the brains of animals which express the therapeutic genes. The development of cell-type-specific vector specific for neurons and brain MVECs will not only be useful for possible future application of gene therapy of AIDS dementia, but also for numerous other disorders of the CNS.